CH482691A - Process for preparing 1,4-disubstituted piperazines - Google Patents

Process for preparing 1,4-disubstituted piperazines

Info

Publication number
CH482691A
CH482691A CH1141863A CH1141863A CH482691A CH 482691 A CH482691 A CH 482691A CH 1141863 A CH1141863 A CH 1141863A CH 1141863 A CH1141863 A CH 1141863A CH 482691 A CH482691 A CH 482691A
Authority
CH
Switzerland
Prior art keywords
preparing
disubstituted piperazines
piperazines
disubstituted
Prior art date
Application number
CH1141863A
Other languages
French (fr)
Inventor
Stephen Tomcufcik Andrew
Frank Fabio Paul
May Hoffman Arlene
Original Assignee
American Cyanamid Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by American Cyanamid Co filed Critical American Cyanamid Co
Priority to CH842566A priority Critical patent/CH499524A/en
Priority to CH1174870A priority patent/CH514608A/en
Priority to CH735968A priority patent/CH484160A/en
Publication of CH482691A publication Critical patent/CH482691A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B43/00—Preparation of azo dyes from other azo compounds
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
CH1141863A 1963-04-04 1963-09-16 Process for preparing 1,4-disubstituted piperazines CH482691A (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CH842566A CH499524A (en) 1963-04-04 1963-09-16 Anti-protozoal piperazine derivs
CH1174870A CH514608A (en) 1963-04-04 1963-09-16 Anti-protozoal piperazine derivs
CH735968A CH484160A (en) 1963-04-04 1963-09-16 Process for preparing 1,4-disubstituted piperazines

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US27053463A 1963-04-04 1963-04-04
US27053763A 1963-04-04 1963-04-04
US27053663A 1963-04-04 1963-04-04
US37971464A 1964-07-01 1964-07-01
US468143A US3331830A (en) 1963-04-04 1965-06-29 1-substituted-4-substituted aminoalkylene piperazines
US468142A US3331843A (en) 1963-04-04 1965-06-29 1-substituted-4-substituted aminoalkylene piperazines

Publications (1)

Publication Number Publication Date
CH482691A true CH482691A (en) 1969-12-15

Family

ID=27559486

Family Applications (1)

Application Number Title Priority Date Filing Date
CH1141863A CH482691A (en) 1963-04-04 1963-09-16 Process for preparing 1,4-disubstituted piperazines

Country Status (13)

Country Link
US (2) US3331843A (en)
BE (1) BE637271A (en)
BR (1) BR6352303D0 (en)
CH (1) CH482691A (en)
DE (1) DE1445425A1 (en)
FI (2) FI41280C (en)
FR (1) FR3708M (en)
GB (1) GB1047935A (en)
LU (1) LU44424A1 (en)
MC (1) MC435A1 (en)
NL (1) NL297170A (en)
NO (1) NO117694B (en)
SE (2) SE320667B (en)

Families Citing this family (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1165283A (en) * 1967-01-17 1969-09-24 Science Union & Cie New Purine Derivatives and processes for prepararing them
US3491098A (en) * 1967-05-29 1970-01-20 Sterling Drug Inc 1-((imidazolyl)-lower-alkyl)-4-substituted-piperazines
GB1279843A (en) * 1969-05-23 1972-06-28 Science Union & Cie Benzamidoethyl-piperazines and process for their preparation
US4081542A (en) * 1975-04-21 1978-03-28 Merck & Co., Inc. Piperazinylpyrazines
CH653021A5 (en) * 1981-04-24 1985-12-13 Delalande Sa PIPERIDINO, PIPERAZINO AND HOMOPIPERAZINO DERIVATIVES, N-SUBSTITUTED BY AN AROMATIC HETEROCYCLIC GROUP, THEIR PREPARATION METHOD AND THERAPEUTIC COMPOSITION CONTAINING THEM.
US4457931A (en) * 1982-09-27 1984-07-03 Selvi & C. S.P.A. Piperazine derivatives with anticholinergic and/or antihistaminic activity
HUT43600A (en) * 1985-06-22 1987-11-30 Sandoz Ag Process for production of new thiazole derivatives and medical compound containing those
US5057517A (en) * 1987-07-20 1991-10-15 Merck & Co., Inc. Piperazinyl derivatives of purines and isosteres thereof as hypoglycemic agents
US4977156A (en) * 1988-07-26 1990-12-11 The Dow Chemical Company Amino piperazine esters showing biocidal activity
US5032604A (en) * 1989-12-08 1991-07-16 Merck & Co., Inc. Class III antiarrhythmic agents
JP3193560B2 (en) * 1993-04-16 2001-07-30 明治製菓株式会社 New benzoxazole derivatives
EP1165082A4 (en) * 1999-03-03 2002-06-12 Merck & Co Inc Inhibitors of prenyl-protein transferase
CA2362494A1 (en) 1999-03-03 2000-09-08 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
WO2000078716A1 (en) * 1999-06-24 2000-12-28 Toray Industries, Inc. α1B-ADRENERGIC RECEPTOR ANTAGONISTS
AU6936500A (en) * 1999-08-24 2001-03-19 Regents Of The University Of California, The Non-quinoline inhibitors of malaria parasites
OA12789A (en) * 2002-03-13 2006-07-10 Janssen Pharmaceutica Nv Carbonylamino-derivatives as novel inhibitors of histone deacetylase.
EA007270B1 (en) * 2002-03-13 2006-08-25 Янссен Фармацевтика Н.В. Piperazinyl-, piperadinyl- and morpholinyl-derivatives as novel inhibitors of histone deacetylase
PL212089B1 (en) 2002-03-13 2012-08-31 Janssen Pharmaceutica Nv New inhibitors of histone deacetylase
JP4725945B2 (en) 2002-03-13 2011-07-13 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Sulfonylamino derivatives as novel inhibitors of histone deacetylase
BRPI0512676B8 (en) * 2004-07-28 2021-05-25 Janssen Pharmaceutica Nv substituted indolyl alkyl amine derivatives as histone deacetylase inhibitors, pharmaceutical composition comprising them, their preparation processes and use
MY179032A (en) 2004-10-25 2020-10-26 Cancer Research Tech Ltd Ortho-condensed pyridine and pyrimidine derivatives (e.g.purines) as protein kinase inhibitors
UY29177A1 (en) * 2004-10-25 2006-05-31 Astex Therapeutics Ltd SUBSTITUTED DERIVATIVES OF PURINA, PURINONA AND DEAZAPURINA, COMPOSITIONS THAT CONTAIN METHODS FOR THEIR PREPARATION AND ITS USES
WO2006089076A2 (en) 2005-02-18 2006-08-24 Neurogen Corporation Thiazole amides, imidazole amides and related analogues
DK1885710T3 (en) 2005-05-18 2015-11-23 Janssen Pharmaceutica Nv SUBSTITUTED AMINOPROPENYLPIPERIDINE OR MORPHOLINE DERIVATIVES AS UNKNOWN INHIBITORS OF HISTONDEACETYLASE
EP1981875B1 (en) * 2006-01-19 2014-04-16 Janssen Pharmaceutica N.V. Substituted indolyl-alkyl-amino-derivatives as inhibitors of histone deacetylase
ATE432272T1 (en) * 2006-01-19 2009-06-15 Janssen Pharmaceutica Nv AMINOPHENYL DERIVATIVES AS NEW INHIBITORS OF HISTONE DEACETYLASE
CA2630717C (en) 2006-01-19 2015-02-24 Janssen Pharmaceutica N.V. Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase
JP5137848B2 (en) * 2006-01-19 2013-02-06 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase
EP3421471B1 (en) 2006-04-25 2021-05-26 Astex Therapeutics Limited Purine and deazapurine derivatives as pharmaceutical compounds
AU2008277796A1 (en) * 2007-07-19 2009-01-22 F. Hoffmann-La Roche Ag Novel heterocyclyl compounds and their use as chemokine antagonists
TW201446748A (en) * 2007-08-22 2014-12-16 Astrazeneca Ab Cyclopropyl amide derivatives
JP4705695B2 (en) 2007-10-11 2011-06-22 アストラゼネカ アクチボラグ Pyrrolo [2,3-D] pyrimidine derivatives as protein kinase B inhibitors
EP2212310A4 (en) * 2007-10-15 2011-04-20 Elder Pharmaceuticals Ltd An industrially feasible process for the manufacture of bisquinoline derivatives by using substantially pure n-monosubstituted piperazines
TW201039825A (en) * 2009-02-20 2010-11-16 Astrazeneca Ab Cyclopropyl amide derivatives 983
FR2945289A1 (en) * 2009-05-11 2010-11-12 Sanofi Aventis 2-CYCLOAMINO-5- (PYRIDIN-4-YL) IMIDAZO-2,1-B1 DERIVATIVES 1,3,4! THIADIAZOLE, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
WO2011095885A1 (en) * 2010-02-08 2011-08-11 Matrix Laboratories Ltd. An improved process for the preparation of piperaquine
EP2536702A4 (en) * 2010-02-18 2013-07-10 Astrazeneca Ab New crystalline form of a cyclopropyl benzamide derivative
EP2536701A4 (en) * 2010-02-18 2014-05-07 Astrazeneca Ab Solid forms comprising a cyclopropyl amide derivative
HUE047357T2 (en) 2011-04-01 2020-04-28 Astrazeneca Ab Therapeutic treatment
EP2718268B1 (en) 2011-06-06 2016-12-28 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Novel process for the synthesis of 7-chloro-4-(piperazin-1-yl)-quinoline
KR102035361B1 (en) 2011-11-30 2019-11-08 아스트라제네카 아베 Combination treatment of cancer
AU2013204533B2 (en) 2012-04-17 2017-02-02 Astrazeneca Ab Crystalline forms
ES2879995T3 (en) 2015-12-10 2021-11-23 Ptc Therapeutics Inc Methods for treating Huntington's disease
WO2018226622A1 (en) 2017-06-05 2018-12-13 Ptc Therapeutics, Inc. Compounds for treating huntington's disease
EP3644996B1 (en) 2017-06-28 2023-07-26 PTC Therapeutics, Inc. Methods for treating huntington's disease
CA3067592A1 (en) 2017-06-28 2019-01-03 Ptc Therapeutics, Inc. Methods for treating huntington's disease
JP7399870B2 (en) 2018-03-27 2023-12-18 ピーティーシー セラピューティクス， インコーポレイテッド Compounds to treat Huntington's disease
CN110606830B (en) * 2018-06-14 2022-03-18 珠海润都制药股份有限公司 Method for producing piperaquine phosphate intermediate quinoline piperazine hydrochloride by applying piperazine
WO2020005873A1 (en) 2018-06-27 2020-01-02 Ptc Therapeutics, Inc. Heterocyclic and heteroaryl compounds for treating huntington's disease
US11685746B2 (en) 2018-06-27 2023-06-27 Ptc Therapeutics, Inc. Heteroaryl compounds for treating Huntington's disease

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2513026A (en) * 1950-06-27 Process for preparing same
NL72956C (en) * 1947-11-12
US2861072A (en) * 1952-07-19 1958-11-18 Abbott Lab Preparation of piperazine derivatives
US2794804A (en) * 1955-03-24 1957-06-04 American Cyanamid Co Substituted piperazines and method of preparing the same
US2949431A (en) * 1957-07-17 1960-08-16 Mobay Chemical Corp Preparation of cellular polyurethanes using piperazine catalysts
US3098066A (en) * 1960-03-04 1963-07-16 Ciba Geigy Corp Diaza-heterocyclic guanidine compounds
US3015657A (en) * 1959-05-28 1962-01-02 Charles F Geschickter 1-carbalkoxy-4-(aminoalkanol) piperazines
US3030366A (en) * 1961-01-25 1962-04-17 Lakeside Lab Inc Piperazinoalkyl glycolamides
FR1525M (en) * 1961-07-25 1962-11-16 Ile De France New antiemetic drugs.
US3190883A (en) * 1962-10-05 1965-06-22 Geschickter Fund Med Res Aminoalkanol derivatives of piperazines
US3184382A (en) * 1963-08-12 1965-05-18 Pure Oil Co Method of producing tranquilization by hydroxy-loweralkyl-n-substituted carbamic acid esters

Also Published As

Publication number Publication date
BE637271A (en) 1900-01-01
FI42440B (en) 1970-04-30
US3331830A (en) 1967-07-18
DE1445425A1 (en) 1968-10-31
FI41280B (en) 1969-06-30
SE346316B (en) 1972-07-03
FI41280C (en) 1969-10-10
FR3708M (en) 1965-11-29
BR6352303D0 (en) 1973-07-17
GB1047935A (en) 1966-11-09
FI42440C (en) 1970-08-10
NO117694B (en) 1969-09-15
US3331843A (en) 1967-07-18
MC435A1 (en) 1964-07-06
NL297170A (en) 1900-01-01
LU44424A1 (en) 1963-11-11
SE320667B (en) 1970-02-16

Similar Documents

Publication Publication Date Title
CH482691A (en) Process for preparing 1,4-disubstituted piperazines
CH438294A (en) Process for preparing periplogenin
CH429748A (en) Process for preparing a 2-N-aroyl-2 ', 3'-0-isopropylidene-guanosine
FR1335831A (en) Process for preparing nu- (3, 3-diphenyl-3-alkanoyl) -propylspiro
FR1370795A (en) Process for preparing 3-substituted benzo-gamma-pyrones
FR1397573A (en) Process for preparing 2. 6-dichloro-benzonitrile
FR1403372A (en) Process for preparing substituted 5-aminopyrazols
FR94701E (en) 1,4-Disubstituted piperazines and process for their preparation.
FR1391609A (en) Process for preparing aldehydes
FR1392872A (en) Process for preparing phthaloylpyrrocolines
FR1377140A (en) Process for preparing 2-methyl-2-secondobutylpropanediol-1, 3
FR1405725A (en) Process for preparing 5, 5-dimethyl-4-iminohydantoin
CH414633A (en) Process for preparing 3,4-di-acyl pyridoxines
FR1401077A (en) Improved process for preparing 1, 2, 3, 4-tetrachlorobutane
CH428696A (en) Process for preparing alkyl-cyclopentane-diones
FR1434172A (en) Process for preparing new substituted estrones
FR1356114A (en) Process for preparing trans-dimethylolcyclohexane-1, 4
FR1381649A (en) Process for preparing 3, 19-disubstituted 5-androstenes
FR1376209A (en) Process for preparing trimethylene-1, 3, 5-trisulfone
FR1396616A (en) Improved process for preparing diaminomonoazotriazines
FR1404689A (en) Process for preparing new lactones
FR1394286A (en) Process for preparing oxazinones
FR1397085A (en) Process for preparing 1, 2-dicyanocyclobutane
FR1401076A (en) Process for preparing 1, 2, 3, 4-tetrachlorobutane
CH420166A (en) Process for preparing w-lactams

Legal Events

Date Code Title Description
PL Patent ceased